Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis
Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis
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DOI：
10.1158/0008-5472.can-03-3112
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Alman, BA
中科院分区：
文献类型：
--
作者：
Kong, Y;Poon, R;Alman, BA
基质金属蛋白酶（MMPs）和MMPs组织抑制剂（TIMPs）调节细胞外基质成分的降解，并在选定的肿瘤过程的进展中发挥重要作用。局部侵袭性软组织肿瘤，侵袭性纤维瘤病（也称为硬纤维瘤），是由导致β-连环蛋白介导的T细胞因子（tcf）依赖性转录活性的突变引起的。由于β-连环蛋白可以调节MMP的表达，我们研究了几种MMP和TIMP在Apc+/Apc 1638 N小鼠侵袭性纤维瘤病肿瘤中的表达。与正常纤维组织相比，MMP-3和TIMP-1在肿瘤中差异调节（分别为5倍和0.5倍）。来自肿瘤细胞的条件培养基显示出增加的降解胶原的能力，并且使用GM 6001抑制MMP降低了肿瘤细胞通过Matrigel侵入的能力。用GM 6001处理Apc/Apc 1638 N小鼠或与过表达Timp-1的转基因小鼠杂交均导致肿瘤体积显著减小。令人惊讶的是，Timp-1的过表达也导致肿瘤数量增加50%。尽管TIMP-1可以诱导某些细胞类型的生长刺激作用，但我们发现，与不表达TIMP-1转基因的小鼠相比，TIMP-1转基因小鼠中肿瘤细胞的增殖或凋亡率没有差异，这表明TIMP-1通过另一种机制促进侵袭性纤维瘤病肿瘤形成。这些数据表明，基质金属蛋白酶在调节间充质细胞的侵袭性和调节侵袭性纤维瘤病肿瘤进展中起着至关重要的作用。因为这是一种局部浸润性肿瘤，MMP抑制可以减缓肿瘤生长，并可能被证明是一种有效的辅助治疗。
Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate the degradation of extracellular matrix components and play important roles in the progression of select neoplastic processes. The locally invasive soft tissue tumor, aggressive fibromatosis (also called desmoid tumor), is caused by mutations resulting in beta-catenin-mediated T-cell factor (tcf)-dependent transcriptional activity. Because beta-catenin can regulate MMP expression, we investigated the expression of several MMPs and TIMPs in aggressive fibromatosis tumors that develop in Apc+/Apc1638N mice. Mmp-3 and Timp-1 were differentially regulated (5-fold and 0.5-fold, respectively) in tumors compared with normal fibrous tissue. Conditioned media from tumor cells showed an increased ability to degrade collagen, and inhibition of MMPs using GM6001 decreased the ability of the tumor cells to invade through Matrigel. Both the treatment of Apc/Apc1638N mice with GM6001 or crossing with a transgenic mouse that overexpresses Timp-1 resulted in a significant reduction in tumor volume. Surprisingly, overexpression of Timp-1 also resulted in a 50% increase in tumor number. Although TIMP-1 can induce growth stimulatory effects in some cell types, we found no difference in proliferation or apoptosis rate in cells from tumors that developed in the Timp-1-transgenic mice compared with mice that did not express the Timp-1 transgene, suggesting that TIMP-1 promotes aggressive fibromatosis tumor formation through an alternate mechanism. These data suggest that MMPs play a crucial role in regulating the invasiveness of mesenchymal cells and in modulating aggressive fibromatosis tumor progression. Because this is a locally invasive tumor, MMP inhibition could slow tumor growth and may prove to be an effective adjuvant therapy.